NDUFAF4

NDUFAF4
Identifiers
Aliases	NDUFAF4 , C6orf66, HRPAP20, My013, bA22L21.1, HSPC125, NADH:ubiquinone oxidoreductase complex assembly factor 4, MC1DN15
External IDs	OMIM: 611776 MGI: 1915743 HomoloGene: 40928 GeneCards: NDUFAF4
Gene location (Human)
Chr.	Chromosome 6 (human)
End	96,897,891 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	24,905,001 bp
RNA expression pattern
	Top expressed in
	pons; ; right ventricle; ; left ventricle; ; endothelial cell; ; biceps brachii; ; gastrocnemius muscle; ; cerebellar vermis; ; oocyte; ; Brodmann area 23; ; prefrontal cortex;
	Top expressed in
	atrioventricular valve; ; endocardial cushion; ; digastric muscle; ; intercostal muscle; ; sternocleidomastoid muscle; ; temporal muscle; ; myocardium of ventricle; ; secondary oocyte; ; Paneth cell; ; vastus lateralis muscle;
	More reference expression data
	n/a
Gene ontology
Molecular function	protein binding ; calmodulin binding ;
Cellular component	mitochondrial inner membrane ; mitochondrial membrane ; mitochondrion ; membrane ;
Biological process	NADH dehydrogenase complex assembly ; mitochondrial respiratory chain complex I assembly ;
	Sources:Amigo / QuickGO
Orthologs
	29078
	68493
	ENSG00000123545
	ENSMUSG00000028261
	Q9P032
	Q9D1H6
	NM_014165
	NM_026742
	NP_054884
	NP_081018
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated March 04, 2023

NADH:ubiquinone oxidoreductase complex assembly factor 4, (NDUFAF4) also known as Hormone-regulated proliferation-associated protein of 20 kDa, (HRPAP20) or C6orf66 is a protein that in humans is encoded by the NDUFAF4 gene.^[5]^[6] NDUFAF4 is a mitochondrial assembly protein involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.^[7]^[8] Mutations in this gene have been associated with complex I deficiency and infantile mitochondrial encephalomyopathy.^[5]^[6]^[8] Elevations in HRPAP20 have also been implicated in breast cancer.^[9]

Structure

NDUFAF4 is located on the q arm of chromosome 6 in position 16.1 and has 3 exons.^[5] The NDUFAF4 gene produces a 23.7 kDa protein composed of 203 amino acids.^[10]^[11] HRPAP20 is a phosphoprotein, containing a phosphate group attachment and, potentially, multiple kinase recognition sequences. Additionally, it has a CaM-binding sequence that allows it to interact with calmodulin (CaM), which itself is involved in numerous cellular processes.^[9]

Function

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. NDUFAF4 encodes a complex I assembly factor that is important for the correct assembly and function of complex I.^[5] NDUFAF4 colocalizes, comigrates to several assembly intermediates, and is codependent with NDUFAF3 from the early to late stages of complex I assembly. In addition to their close interactions with each other, NDUFAF4 and NDUFAF3 interact with NDUFS2, NDUFS3, NDUFS8, and NDUFA5 in a translation-dependent early assembly mechanism.^[12] NDUFAF4 has also been shown to play a role in growth and apoptosis regulation through a CaM-mediated mechanism involving MMP-9 secretion.^[9]

Clinical significance

Mutations in NDUFAF4 (HRPAP20) have been associated with mitochondrial complex I deficiency,^[5] infantile mitochondrial encephalomyopathy.^[8] Additionally, research analyzing HRPAP20's effect on human cancer cells have suggested that it plays a role in tumor metastasis, malignant progression, and breast cancer.^[9]

Mitochondrial diseases are disorders that are the result of the dysfunction of the mitochondrial respiratory chain. They can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.^[6]^[13] Pathogenic mutations have been linked to changes in a 2.6 Mb critical region (97.17–99.77 Mb) on chromosome 6 and have included a T→C substitution at p. 194 in exon 2 that predicts a Leu65Pro variant. Clinically, NDUFAF4 mutations have been associated with infantile mitochondrial encephalomyopathy, with lactic acidosis, nystagmus, hypotonia, cardiomyopathy, cerebral atrophy, and generalized tonic-clonic convulsions as some possible symptoms.^[8]

HRPAP20 was found to be significantly elevated in patient breast tumors as compared to normal tissue. Further analysis using tumor cell lines with constitutively expressed HRPAP20 suggests that it increases the invasiveness, proliferation, and apoptotic suppression of breast cancer cells. This is often indicative of tumor metastasis and malignant progression.^[9]

Interactions

NDUFAF4 (HRPAP20) has been shown to interact closely with NDUFAF3 as well as with NDUFS2, NDUFS3, NDUFS8, and NDUFA5 in the mitochondrial inner membrane.^[12] HRPAP20 also interacts with calmodulin (CaM) in a mechanism that results in increased MMP-9 secretion, associated with increased invasiveness in breast cancer cells.^[9] In addition to co-complexes, NDUFAF4 has protein-protein interactions with WDR26.^[14]

Related Research Articles

MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in human MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).

NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene. This gene encodes a nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase. Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the NDUFS3 gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase. Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the NDUFS8 gene. The NDUFS8 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with Leigh syndrome.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial (NDUFS2) also known as NADH-ubiquinone oxidoreductase 49 kDa subunit is an enzyme that in humans is encoded by the NDUFS2 gene. The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase. Mutations in this gene are associated with mitochondrial complex I deficiency.

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 is a protein that in humans is encoded by the NDUFA1 gene. The NDUFA1 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in the NDUFA1 gene are associated with mitochondrial Complex I deficiency.

NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the NDUFS1 gene. The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and is important for mitochondrial oxidative phosphorylation. Mutations in this gene are associated with complex I deficiency.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial, also knowns as NADH-ubiquinone oxidoreductase 20 kDa subunit, Complex I-20kD (CI-20kD), or PSST subunit is an enzyme that in humans is encoded by the NDUFS7 gene. The NDUFS7 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6, also known as complex I-B17, is a protein that in humans is encoded by the NDUFB6 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6, is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the NDUFA2 gene. The NDUFA2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in the NDUFA2 gene are associated with Leigh's syndrome.

FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the FOXRED1 gene. FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in FOXRED1 have been associated with Leigh syndrome and infantile-onset mitochondrial encephalopathy.

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 is an enzyme that in humans is encoded by the NDUFA8 gene. The NDUFA8 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 is an enzyme that in humans is encoded by the NDUFS5 gene.

Complex I intermediate-associated protein 30, mitochondrial (CIA30), or NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1 (NDUFAF1), is a protein that in humans is encoded by the NDUFAF1 or CIA30 gene. The NDUFAF1 gene encodes a human homolog of a Neurospora crassa protein involved in the assembly of complex I. The NDUFAF1 protein is an assembly factor of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the NDUFAF1 gene are associated with hypertrophic cardiomyopathy, leukodystrophy, and cardioencephalomyopathy.

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3, also known as 2P1, E3-3, or C3orf60, is a protein that in humans is encoded by the NDUFAF3 gene. NDUFAF3 is a mitochondrial assembly protein involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with severe complex I deficiency and Leigh syndrome.

NADH:ubiquinone oxidoreductase complex assembly factor 2 (NDUFAF2), also known as B17.2L or NDUFA12L is a protein that in humans is encoded by the NDUFAF2, or B17.2L, gene. The NDUFAF2 protein is a chaperone involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with progressive encephalopathy and Leigh disease resulting from mitochondrial complex I deficiency.

NADH:ubiquinone oxidoreductase complex assembly factor 6 is a protein that in humans is encoded by the NDUFAF6 gene. The protein is involved in the assembly of complex I in the mitochondrial electron transport chain. Mutations in the NDUFAF6 gene have been shown to cause Complex I deficiency, Leigh syndrome, and Acadian variant Fanconi Syndrome.

NADH:ubiquinone oxidoreductase complex assembly factor 5, also known as Arginine-hydroxylase NDUFAF5, or Putative methyltransferase NDUFAF5, is a protein that in humans is encoded by the NDUFAF5 gene. The NADH-ubiquinone oxidoreductase complex of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene.

Protein arginine methyltransferase NDUFAF7, mitochondrial, also known as NADH:ubiquinone oxidoreductase complex assembly factor 7 (NDUFAF7),MidA, C2orf56, or PRO1853, is a protein that in humans is encoded by the NDUFAF7 gene. NDUFAF7 is a methyltransferase mitochondrial assembly enzyme involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in NDUFAF7 have been associated with pathologic myopia and complex I deficiency.

NADH:ubiquinone oxidoreductase complex assembly factor 8 is a protein that in humans is encoded by the NDUFAF8 gene. This protein stabilizes NDUFAF5 during assembly of mitochondrial Complex I.

References

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